Derivatives of berberine

ABSTRACT

Novel derivatives of berberine of the formula:   WHEREIN RCO represents a cinnamoyl group which may be substituted with chloro, acetoxy, methoxy or methylenedioxy groups on the benzene ring, and A represents an anion. The compounds inhibit the growth of transplanted sarcoma strain in mice.

United States Patent [191 Shimada et al.

[ 51 May 20, 1975 1 DERIVATIVES OF BERBERINE 22 Filed: Aug. 22, 1973 211 Appl. No.2 390,402

[30] Foreign Application Priority Data Aug. 25, 1972 Japan 47-85651 [52] U.S. Cl. 260/240 .1; 424/258; 260/286 Q;

[51] Int. Cl C07d 35/28 [58] Field of Search 260/240 J [56] References Cited OTHER PUBLICATIONS Shamma et al., J. Am. Chem. Soc., Vol. 92, pp. 4943 to 4949 (1970).

Sun et al., Chemical Abstracts, Vol. 63, Col. 7062 (1965), (abst. of original in 'Yao Hseuh Hsueh Pao, Vol. 12, pp. 314-318 (1965).

Chemical Abstracts subject index, Vol. 63, P. 473 s (1965).

Primary Examiner-John D. Randolph Attorney, Agent, or Firm-Millen, Raptes & White [57 ABSTRACT Novel derivatives of berberine of the formula:

OOCR

OCH

wherein RCO represents a cinnamoyl group which may be substituted with chloro, acetoxy, methoxy or methylenedioxy groups on the benzene ring, and A represents an anion. The compounds inhibit the growth of transplanted sarcoma strain in mice.

6 Claims, No Drawings DERllVA'Il /ES OF BERBERINE This invention relates to novel derivatives ofberben ine of the formula:

with a functional derivati e of a cinnamic acid which may be substituted with chloro, hydroxy, acetoxy, methoxy or methylenedioxy groups on the benzene ring.

According to the present invention, it has been found that berberrubine, which is easily obtainable by heating berberine chloride at about 190C in an inert medium such as nitrogen, carbon dioxide or liquid paraffin, may be acylated with a functional derivative of cinnamic acid or an appropriately substituted derivative thereof to give the novel derivatives of berbcrine of the formula I.

As the substituted cinnamic acids, 4-chloro-, 3, 4- dimethoxy-, or 3, 4- methylendioxycinnamic acid, or acetylfclulic acid, namely 4- acetoxy-3- methoxycinnamic acid, may be used.

As the functional derivatives of cinnamic acid or the substituted cinnamic acid, esters such as methyl or ethyl esters, anhydrides, or halides such as chloride, bromide or iodide may be used.

Examples of the anion of A are halides such as chloride, bromide or iodide, or hydroxide ions.

The reaction proceeds at an elevated temperature in a solvent such as chloroform, ethylenechloride or benzene, optionally in the presence of an acid acceptor such as pyridine, piperazine, quinoline or other tertiary amines.

According to the process as described above, for example, the following final products may be obtained:

9-demethyl-9--cinnamoylberberine chloride,

9-demethyl-9-acetylfeluloyberberine chloride, 9-demethyl-9-(4-5hlorocinnamoyl) berberine chloride,

9-demethyl-9-( 3 ,4'-dimethoxycinnamoyl) berberine chloride,

and 9-demethyl-'9-( 3 4-neth lenedioxycinnamoyl) berberine chloride.

Throughout the speciiication and claims, it should be understood that the nomenclature of O demethylberberine represents berberines with a methyl group removed from the methoxy group at the 9- position.

The novel compounds of the present invention effectively inhibit the growth of transplanted sarcoma in mice.

For example, sarcoma strain 180 was transplanted to peritoneum of mice and the test compound .was administercd intraperitioneally to mice once a day for 5 consecutive days. After one week abdominal ascites was collected and the total volume of sarcoma cells was compared with that of control.

in the above test, 9-demethyl-9-cinnamoylberberine chloride showed a inhibition rate of 95 percent upon 5 administrations thereof at a dose of BOmg/kg/day and 9-demethyl-9-acetylfeluloylberberine chloride showed a inhibition rate of 90 percent at a dose of ZSmg/kg/day.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. T he following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

Example 1 15g of berberrubine was dissolved in a mixture of 800ml of chloroform and 30ml of pyridine under heating. To this solution was added dropwise lOg of cinnamoyl chloride in ml of chloroform. The mixture was refluxed for 4 hours and cooled, and the resulting crystals were collected and recrystallized from ethanol. 8.2g of 9-demethyl-9-cinnamoylberberine chloride melting at 2l2-2l4C with decomposition was obtained. The product showed a single spot at an Rf=0. l 7 on thin layer chromatography thereof (Silica gel G, methanol: Wate1==3:l), and an absorption of v C=0 1750mm 1 in the infra-red absorption spectrum.

Example 2 10g of berberrubine was dissolved in a mixture of 350ml of chloroform and 26ml of pyridine under heating. To this solution was added dropwise 10g of acetylfeluloyl chloride in 100ml of chloroform. The mixture was refluxed for 5 hours and cooled, and the resulting crystals were collected and recrystallized from ethanol. 5.3g of yellow needles of 9-demethyl-9- acetylfeluloylberberine chloride melting at 2l5-l28C with decomposition was obtained. The product showed a single spot at an Rf=4l20 on the thin layer chromatography thereof (Silica gel G, methanol: water-=3:l), and an absorption of v C=O l740cm 1 on the infra-red absorption specturm.

Example 3 20g of berberrubine was dissolved in a mixture of l l. of chloroform and 50ml. of pyridine under heating and 50ml. of chloroform was distilled off to remove water present in the azeotropic mixture. To the solution was added dropwise 16g of p-chlorocinnamoyi chloride in 100ml. of chloroform. The mixture was refluxed for 2 hours and evaporated to reduce the volume.

Crystals which formed upon cooling were collected and recrystallized from ethanol, whereby 10.5g

yellow needles of 9-dernethyl-9-( 4 chlorocinnamoyl) berberine chloride melting at 233235C with decomposition was obtained. The product showed a single spot at an Rf=0.l5 on thin layer chromatography thereof (Silica gel G, methanol: water=3:l), and an absorption of v C=O l735cm in the infra-red absorption spectrum.

Example 4 g of berberrubine was dissolved in a mixture of 600ml of chloroform and 50ml of pyridine under heating and 50ml of chloroform was distilled off to remove water present in the azeotropic mixture.

To the solution was added dropwise 10g of 3, 4- dimethoxycinnamoyl chloride in 100ml of chloroform. The mixture was refluxed for 2 hours and cooled. The resulting crystals were collected and recrystallized from ethanol, whereby 6.1 g of yellow needles of 9-demethyl-9-(3',4-dimethoxycinnamoyl) berberine chloride was obtained. The product showed a single spot at an RF=0.16 on thin layer chromatography thereof (Silica gel G, methanol: water=3:1), and an absorption of v C=O 1725 in the infra-red absorption spectrum.

Example 5 10g of berberrubine was dissolved in a mixture of 600ml of chloroform under heating. To this solution was added dropwise 10g of 3, 4-methylenedioxycinnamoyl chloride. The mixture -was refluxed for 3 hours and cooled. The resulting crystals were collected and recrystallized from methanol, whereby 12g of yellow crystals of 9-demethyl-9-(3, 4-methylenedioxycinnamoyl) berberine chloride was obtained. The product showed a single spot at an Rf=0.l6 on thin layer chromatography thereof (Silica gel G, methanol water=3;l and an absorption of v C=O l740cm in the infra-red absorption spectrum.

Various other examples and modifications of the foregoing examples can be devised by the person skilled in the art after reading the foregoing disclosure and the appended claims without departing from the spirit and scope of the invention. All such further examples and modifications thereof are included within the scope of said claims.

WHAT IS CLAIMED IS:

1. A derivative of berberine of the formula:

wherein RCO represents a cinnamoyl group which may be substituted with chloro, acetoxy, methoxy or methylenedioxy groups on the benzene ring, and A repre sents an anion.

2. A compound according to claim 1, wherein the RC0 group is cinnamoyl and A is chloride.

3. A compound according to claim 1, wherein the RC0 group is acetylfeluloyl and A is chloride.

4. A compound according to claim 1, wherein the RC0 group is 4-chlorocinnamoyl and A is chloride.

5. A compound according to claim 1, wherein the RC0 group is 3, 4-dimethoxycinnamoyl and A is chloride.

6. A compound according to claim 1, wherein the RC0 group is 3, 4-methylenedioxycinnamoyl and A is 

1. A DERIVATIVE OF BERBERINE OF THE FORMULA:
 2. A compound according to claim 1, wherein the RCO group is cinnamoyl and A is chloride.
 3. A compound according to claim 1, wherein the RCO group is acetylfeluloyl and A is chloride.
 4. A compound according to claim 1, wherein the RCO group is 4-chlorocinnamoyl and A is chloride.
 5. A compound according to claim 1, wherein the RCO group is 3, 4-dimethoxycinnamoyl and A is chloride.
 6. A compound according to claim 1, wherein the RCO group is 3, 4-methylenedioxycinnamoyl and A is chloride. 